Excessive inflammation at mucosal surfaces in the airway disrupts normal physiology and can lead to acute lung injury (ALI) and its most severe form the acute respiratory distress syndrome (ARDS). The pulmonary inflammatory response during these clinical syndromes is characterized by a considerable neutrophil infiltrate that produces pro-inflammatory cytokines and tissue destructive factors. Ultimately, alveolar-capillary integrity and gas exchange become impaired. A major etiology known to induce ALI/ARDS is the exposure of the airway mucosal surface to components of the cell wall of Gram-negative bacteria, in particular, lipopolysaccharide (LPS). Emerging evidence suggests that ectodomain shedding, which is defined as the proteolytic conversion of a cell surface protein into a soluble extracellular domain fragment, is an important post-translational mechanism involved in regulating inflammation. ADAM17 is a key protease that mediates ectodomain shedding;however, inactivating its gene in all cells of mice is lethal, and therefore little is currently known about its role in regulating inflammation in vivo. To address this critical gap in our understanding, we have generated mice in which only the leukocytes lack functional ADAM17. These animals are viable and our studies have demonstrated that ADAM17 is the principle mechanism of shedding by mature neutrophils and macrophages of the broad functioning adhesion protein L-selectin, the pleiotropic cytokine TNFa, and its two receptors TNFRI and TNFRII, all of which have important functions in LPS-induced lung inflammation. Hence, we hypothesize that ADAM17 plays a central role in regulating LPS-induced, acute pulmonary inflammation. The aim of our study is to identify and analyze inflammatory events in the LPS-exposed respiratory tract of mice that are altered when the shedding of ADAM17 substrates by leukocytes is prevented, and investigate the mechanisms of these alterations. Our objectives include comparative studies in conditional ADAM17 knock-out mice and control mice using a model of airway exposure to LPS, which mimics features typical of the clinical condition ALI/ARDS. Multiplexed arrays will be used to broadly survey cytokine and chemokine production in the inflamed lungs to determine the cytokine/chemokine network promoted by leukocyte- expressed ADAM17 in a temporal manner. In addition, we will test whether and how ADAM17 is involved in neutrophil recruitment into the inflamed lungs by measuring their accumulation in the lung blood vessels, brochoalveolar lavage fluid, and in the interstitial spaces of the lung. Overall, we anticipate that our study will provide novel insights into the mechanisms by which ADAM17 regulates lung inflammation, and will allow for the design of new treatment strategies for ALI and ARDS. . The immune system's initial response to infection is the recruitment of leukocytes and initiation of inflammation, which, though generally beneficial, can be harmful when overly exuberant. One etiology known to induce the acute respiratory distress syndrome (ARDS) is the exposure of the airway mucosal surface to components of the cell wall of Gram-negative bacteria and in particular lipopolysaccharide (LPS). We hypothesize that leukocyte-expressed ADAM17 plays a critical role in regulating LPS-induced acute pulmonary inflammation and may serve as a therapeutic target to prevent its over-activation. The overall goal of this proposal is to understand the influences of ADAM17 expressed by leukocytes on the early inflammatory response in the lungs directly exposed to LPS.